tbuckley/cabot-search huggingface dataset:
Abstract 6650: Cell-based assay to support development and characterization of new drugs in immuno-oncology
Authors: Mohammad Haque, Safnas Abdul Salam, Shawn McGinley, Haiching Ma, jianghong Wu
Journal: Cancer Research (2023)

Abstract The years since 2009 have seen tremendous progress in unlocking the curative potential of the immune system for the treatment of cancer. Much of that revolution in immuno-oncology has been fueled by the clinical success of immune checkpoint inhibitors, targeting cytokines, antibody dependent cell cytotoxicity and complement dependent cytotoxicity via the T cell activation. Reaction biology has established state-of-art high throughput screening procedures for measuring the ability of new Biologics or compounds to activate T cells. Antibody Dependent Cell Cytotoxicity (ADCC), T cell activation assay (NFAT), immune checkpoint inhibitor assay (PD-1/PD-L1 blockade bioassay), cytokines activation assay and Complement Dependent Cytotoxicity (CDC) are commonly used for drug discovery industry. ADCC is a desirable mechanism for killing target cells using antibody-based drugs. T cell activation assay can be used for the discovery and development of novel biologics and cell therapies aimed at inducing, strengthening and/or engineering T cell response. Blocking of immune inhibitory receptors by their respective ligands on an adjacent cell inhibits TCR mediated proliferation, transcriptional activation and cytokines production. Biologics or compounds designed for measuring the stimulatory or inhibitory function of cytokines are promising in the field of immune oncology. Reaction Biology developed biochemical assays for PD-1/PD-L1, CTLA4/CD80 and CTLA4/CD86 to screen immune checkpoint inhibitors. All of these screening procedures and experimental methods will help to identify new therapeutic biologics or compounds for drug discovery in immune-oncology field. Citation Format: Mohammad Haque, Safnas Abdul Salam, Shawn McGinley, Haiching Ma, jianghong Wu. Cell-based assay to support development and characterization of new drugs in immuno-oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6650.
Abstract 1459: Nanocage delivered engineered destabilized 3UTR ARE of cMYC inhibits triple negative breast cancer growth and metastasis <i>in vivo</i> by targeting cMYC and downregulating STAT5A5B
Authors: Chidiebere U. Awah, Joo Sun Mun, Baris Boylu, Alooka Paragodaarachchi, Chika Ochu, Junfei Zhang, Hiroshi Mastui, Olorunseun Ogunwobi
Journal: Cancer Research (2023)

Abstract c-MYC is a master transcription factor overexpressed in more than 70% of human cancers including breast cancers (TNBC), lung cancers, brain tumors, prostate cancers, lymphomas, pediatrics cancers, pancreatic cancers, colorectal cancers, and ovarian cancers. Yet there is no clinically approved drug that directly targets it. The lack of direct clinically approved inhibitors of c-MYC is a significant biological and clinical question that needs urgent attention, especially in the context of aggressive cancers such as MYC driven triple negative breast cancer. In the USA, TNBC accounts for 10.34% of breast cancers, in China the rate is at 14%, and in African Americans the rate is 40%. We engineered the stable polyU sequences on the 3’UTR of c-MYC into unstable forms and specifically destabilized and degraded c-MYC transcript and protein and controlled primary tumor and metastasis in vivo. We developed three c-MYC destabilizing constructs that were effective in TNBC. They specifically destabilized c-MYC transcript, degraded c-MYC protein and the transcription factors STAT5A/B with increased expression of active caspase 3/7 leading to cancer cell death. In vivo, we delivered nanocage complexed with the MYC destabilizing constructs into TNBC mice bearing tumor and achieved reduction of primary tumor volume by 60-80%, 80% reduction in secondary tumor metastasis and very significant survival outcome (p&amp;lt;0.0001). Mechanistically, the destabilization of c-MYC degraded c-MYC and its super enhancer interacting partner, STAT5A/B, in primary tumors and metastatic tumors. Taken together, we have developed a novel therapy for TNBC and uncovered c-MYC super enhancer STAT5A/B interaction as the target Citation Format: Chidiebere U. Awah, Joo Sun Mun, Baris Boylu, Alooka Paragodaarachchi, Chika Ochu, Junfei Zhang, Hiroshi Mastui, Olorunseun Ogunwobi. Nanocage delivered engineered destabilized 3UTR ARE of cMYC inhibits triple negative breast cancer growth and metastasis in vivo by targeting cMYC and downregulating STAT5A5B [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1459.
Abstract 5834: The pro-tumoral function of cancer-associated mesothelial cells
Authors: Maeva Chauvin
Journal: Cancer Research (2023)

Abstract Cancer-associated mesothelial cells have emerged as significant contributors to the tumor microenvironment, influencing tumor growth and immune evasion. Mesothelial cells are the first point of contact with ovarian cancer cells during peritoneal spread. Peritoneal mesothelial cells also play an essential role in immune surveillance. However, the mechanism by which cancer and mesothelial cells within the tumor microenvironment coordinate growth and immune evasion remains poorly understood. To study the role of mesothelial cells in the tumor microenvironment, we have recently generated novel syngeneic mouse models of high-grade serous ovarian cancer, which were derived from Fallopian tube epithelium, and bear human-relevant mutational genotypes. Analysis of one such model (CCNE1 amplified) using single-cell transcriptomics in omental metastases revealed specific expression of the anti-Mullerian hormone type II receptor (Amhr2) in cancer-associated mesothelial cells, whereas normal omental mesothelium does not express Amhr2. Co-culture of cancer cells with normal omental mesothelial cells induces AMHR2 expression along with a pro-tumorigenic cancer-associated mesothelial cell phenotype. Overexpression of AMHR2 in a human immortalized mesothelial cell line significantly modulated the expression of genes involved in immune response pathways, remodeling of extra-cellular matrix, and secretion of growth factors by RNAseq and qPCR. Furthermore, we showed that anti-Mullerian hormone (AMH) (the ligand of AMHR2), is secreted by ovarian cancer cells and further downregulates the chemoattractant cytokines secreted by CAMCs, thus promoting immunosuppression within the tumor. Finally, implantation of ovarian cancer cells in syngeneic Amhr2-/- hosts results in tumors that grow significantly slower than those implanted in wild-type hosts. Together these data suggest AMHR2 is a specific marker of CAMCs, whose expression is necessary for the reprogramming of mesothelial cells into CAMCs. The AMH-AMHR2 axis mediates paracrine signaling between cancer cells and CAMCs within the tumor microenvironment to promote tumor growth and immune evasion. These results suggest that AMHR2 could be a highly specific target to enhance immunotherapies in ovarian cancer. Citation Format: Maeva Chauvin. The pro-tumoral function of cancer-associated mesothelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5834.
Abstract 6683: Genetic alterations of circulating tumor DNA in advanced pancreatic cancer patients receiving 5-fluorouracil based chemotherapy
Authors: SooBeen Heo, Sunhwa Park, Jung Won Chun, Yun-Hee Kim, Jun-Kyu Kang, Hwang-Phill Kim, Sang Myung Woo, Sun-Young Kong
Journal: Cancer Research (2023)

Abstract Background: Pancreatic cancer remains one of the most devastating malignancies due to lack of target therapeutic options for advanced disease. Liquid biopsy which analyzes tumor-related biomarkers in blood, has emerged as an innovative technology. The aim of this study was to identify circulating tumor DNA (ctDNA) mutations in pancreatic adenocarcinoma(PDAC) patients using multi-gene panels. Methods: Total of 45 patients (27 male, median age 63 years) blood samples were obtained at baseline then follow-up after 2 months samples were acquired in 16 patients at National Cancer Center, Korea from November 2021 to April 2022. CtDNA were analyzed by next-generation-sequencing (NGS) panel of 118 genes and the varient allele frequency (VAF) of detected genes were analyzed. Then the association between outcomes of 5FU treated response and survival (overall survival and progression-free survival; OS and PFS) and VAF reduction at follow-up were analyzed. Results: Total of 35 genes with 114 genetic alterations were detected and frequent mutations were as follows: KRAS (29.9%), TP53 (14.9%), GNAS(4.4%), SMAD4(4.4%), AR(3.5%), RNF434(3.5%), ATM(3.5%), BRCA2(2.6%) and PIK3CA(2.6%). The mean VAF level considering all pathogenic variants of 45 patients was 8.9%(range, 0 - 87.2) including 8 patients who were not detected ctDNA mutations in baseline, and the mean VAF was 4.2% (0 - 50.0) at follow-up in 16 patients. With association of clinical response, patients with partial response (PR) and stable disease (SD) were decreased VAF from 11% at baseline to 10% after 2 months, and three (60%) of patients showed clearance of ctDNA. Progressive disease (PD) patients were also decreased VAF 67% after 2 months, however, clearance of ctDNA was only observed in one patient (12.5%). Reduction of ctDNA more than 50% were associated with longer survival as PFS (&amp;gt; 50% reduction groups vs. no reduction group; 5 vs. 3 months, p value=0.903, OS (undefined vs. 6 months, p value =0.180). Conclusions: This study showed most common mutation was KRAS with several other mutations of ctDNA in PDAC, and outcomes represented association with ctDNA. Citation Format: SooBeen Heo, Sunhwa Park, Jung Won Chun, Yun-Hee Kim, Jun-Kyu Kang, Hwang-Phill Kim, Sang Myung Woo, Sun-Young Kong. Genetic alterations of circulating tumor DNA in advanced pancreatic cancer patients receiving 5-fluorouracil based chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6683.
Abstract 6105: Unravelling the mechanistic basis of chromoplexy, a mutational process driving early cancer genome evolution
Authors: Nataliia Serbyn, Myrthe M. Smit, Vimathi S. Gummalla, Gregory J. Brunette, David S. Pellman
Journal: Cancer Research (2023)

Abstract Genome evolution can happen gradually or via bursts of rearrangements. Chromoplexy is an example of a process driving rapid genome evolution. This mutational signature is detected in ~18% of human cancers (PCAWG Consortium, 2020) and is frequently observed in prostate adenocarcinoma, lymphoid malignancies, and thyroid adenocarcinoma. Chromoplexy is inferred to happen as one catastrophic event that generates copy-neutral chains of translocations involving multiple chromosomes (Baca et al., 2013). Existing studies of chromoplexy monitor the outcome of massive cancer genome reorganization, thus early molecular events leading to catastrophic chromosome rearrangements remain elusive. In this work, we aimed to recapitulate molecular mechanisms underlying chromoplexy. For this, we set out to establish a cell line model and use fluorescence-based reporter systems to enrich for and allow isolation of cells containing signatures of chromoplexy. We additionally address whether colocalization of multiple double-strand breaks, for example in transcription hubs or abnormal nuclear structures, might stimulate chained inter- and intra- chromosomal translocations typical for chromoplexy. If successful, this work will provide a mechanistic understanding of an important mutational process driving rapid genome evolution in cancer, congenital disease, and potentially organismal evolution. Citation Format: Nataliia Serbyn, Myrthe M. Smit, Vimathi S. Gummalla, Gregory J. Brunette, David S. Pellman. Unravelling the mechanistic basis of chromoplexy, a mutational process driving early cancer genome evolution. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6105.
Abstract 2218: The molecular mechanism underlying KRAS regulation on STK31 expression in pancreatic ductal adenocarcinoma
Authors: Yuting Liu, Shing Chun Tang, Yangchao Chen
Journal: Cancer Research (2023)

Abstract KRAS is frequently mutated in pancreatic ductal adenocarcinoma (PDAC). However, targeting mutant KRAS is still challenging. Kinase inhibitors are ideal targeted therapeutics for mutant KRAS-driven cancer. In our previous study, an esiRNA screening was prepared to identify some vital kinases that took part in KRAS mutant-driven pancreatic cancer. The STK31 was identified as a potential therapeutic target in KRAS mutant PDAC. This study aimed to investigate the underlying mechanism of STK31 in KRAS mutant PDAC as well as its therapeutic potential. The results demonstrated that STK31 was upregulated in KRAS mutant PDAC patients with poor survival. STK31 was also highly expressed in PDAC cell lines with KRAS mutant background. Inhibition of STK31 in KRAS mutant cell lines significantly reduced PDAC cell proliferation, colony formation, and migration. Gain and loss of function experiments revealed that STK31 was a downstream target of KRAS in PDAC. Pharmacological inhibition of several signaling pathways involved in KRAS showed MAPK/ERK signaling involved in STK31 regulation. Then, further mechanistic study validated that c-Jun, regulated by KRAS/MAPK/ERK signaling, directly regulated the transcription level of STK31 by binding to its promoter region. In summary, our results show that STK31 promotes PDAC cell proliferation under the control of the KRAS/MAPK/ERK/c-Jun transcriptional axis in PDAC. STK31 may act as a potential target in PDAC treatment. Citation Format: Yuting Liu, Shing Chun Tang, Yangchao Chen. The molecular mechanism underlying KRAS regulation on STK31 expression in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2218.
Abstract 4776: NRF2 is overexpressed in esophageal adenocarcinoma and its targeting sensitizes tumor cells to cisplatin through induction of ferroptosis and apoptosis
Authors: Farah Ballout, Heng Lu, Zheng Chen, Tianling Hu, Lei Chen, Wael El-Rifai, Dunfa Peng
Journal: Cancer Research (2023)

Abstract Background: Esophageal adenocarcinoma (EAC) is the predominant type of esophageal cancer in the United States, with the 5-year survival rate is below 20%. EAC develops through Barrett’s esophagus (BE)-dysplasia-carcinoma cascade. Gastroesophageal reflux disease (GERD), where acidic bile salts refluxate into the esophagus, is the main risk factor for the development of BE and its progression to EAC. The NFE2-related factor 2 (NRF2) is the master cellular antioxidant regulator, involving in many cancer hallmarks. Methods and Results: Using western blotting and immunohistochemistry technologies, we detected high NRF2 protein levels in EAC cell lines and primary EAC tissues, as compared with normal esophagus and non-neoplastic Barrett’s esophagus samples. The knockdown of NRF2 using NRF2 specific siRNAs significantly increased oxidative stress in response to cellular stress stimuli by bile salts or cisplatin. This was associated with an increase in DNA damage and inhibition of EAC cell growth. Brusatol, a NRF2 inhibitor, significantly inhibited NRF2 transcriptional activity and downregulated NRF2 target genes. We discovered that in addition to inducing apoptosis, Brusatol alone or in combination with CDDP induced significant lipid peroxidation and ferroptosis as evidenced by reduced xCT and GPX4 expression, two known ferroptosis markers. Moreover, the combination of Brusatol and CDDP significantly inhibited EAC tumor xenografts growth in vivo. We confirmed the in vitro data showing ferroptosis as an important mechanism in the xenografted tumors treated with Brusatol or Brusatol and CDDP combination using IHC staining. Conclusion: Our data support the role of NRF2 in protecting against stress-induced apoptosis and ferroptosis in EACs. Targeting NRF2 in combination with platinum therapy can be an effective strategy for eliminating cancer cells in EAC. Citation Format: Farah Ballout, Heng Lu, Zheng Chen, Tianling Hu, Lei Chen, Wael El-Rifai, Dunfa Peng. NRF2 is overexpressed in esophageal adenocarcinoma and its targeting sensitizes tumor cells to cisplatin through induction of ferroptosis and apoptosis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4776.
Abstract 2154: Differential expression of the PI3K-Akt signaling pathway pre and post chemotherapy in relation to hormonal profile in African women
Authors: Hurette Junie Chansi Kengni
Journal: Cancer Research (2023)

Abstract Background: Breast cancer (BC) is the most common cancer in US and Canadian women. Despite therapeutic advances, it remains the second leading cause of female cancer mortality. Aggressive breast cancers are represented as a clinical (inflammatory BC or locally advanced BC) or as a biopathological form (triple negative BC or HER2+ BC). These aggressive forms have a poor prognosis. In the US, African Americans have a 41% higher BC death rate than Caucasians women. As observed in the US, in African Gabon women, a more aggressive and cases of triple negative BC are found. Aggressive BC are mainly associated with African women. At this stage, chemotherapy is the main therapeutic treatment but chemoresistance is the major hurdle. One solution to chemoresistance would be to found candidates biomarkers that predict therapeutic responses. The goal of our study was to establish an RNA signature that could differentiate chemosensitive from chemoresistant patients in BC African women. Methods: RNA sequencing technique was used to establish expression profiling in African women before and after chemotherapy using three groups of aggressive BC patients treated with: Doxorubicin, 5-Fluorouracil or Navelbine. We first isolated RNA from tissues fixed in paraffin and sequenced it via the Nextseq 2000 system. A tximport (v1.20.0) and DESeq2 (v1.26.0) analysis then identified significantly and differentially expressed transcripts between the different groups. Results: In the doxorubicin group, post-chemotherapy patients had 962 significant genes out of the 46461 transcripts compared to pre-chemotherapy patients. The post-chemotherapy 5-FluoroUracil group had 3723 significant genes out of 43821 transcripts compared to pre-chemotherapy Fluorouracil group and the post-chemotherapy Navelbine group had 980 significant genes out of 44689 transcripts compared to pre-chemotherapy Navelbine group. Relevant overexpressed genes were selected for validation by immunohistochemistry (IHC). We found an enrichment in the KEGG and PI-3K/Akt pathways and observed that Akt downstream substrates were express differently between pre- and post-chemotherapy patients. Conclusion: Our study suggests that some of the overexpressed post chemotherapy genes could serve as biomarkers of aggressive BC. This is the first study in Canada to investigate Doxorubicin, Flurouracile and Navelbine chemoresistance-related genes in African women and could lead to the discovery of diagnostic markers and therapeutic targets. Citation Format: Hurette Junie Chansi Kengni. Differential expression of the PI3K-Akt signaling pathway pre and post chemotherapy in relation to hormonal profile in African women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2154.
Abstract 2265: STING pathway activation by ATR inhibition potentiates the antitumor immune response to anti-PD-L1 antibody in small cell lung cancer
Authors: Triparna Sen
Journal: Cancer Research (2023)

Abstract Introduction: Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer, with a very poor prognosis and limited therapeutic options. Recent clinical trials of immune checkpoint blockade (ICB) combined with chemotherapy delivered only very modest benefit. Here, we identified that ataxia telangiectasia and rad3 related (ATR), the primary activator of the replication stress response, is highly enriched in SCLC and inhibition of ATR induced DNA damage and apoptosis in multiple SCLC models. Methods: In this study, we performed genetic and pharmacological inhibition of ATR in a panel of human and murine SCLC models. Furthermore, we investigated the effect of ATR inhibition either alone or in combination with PD-L1 blockade either as a first-line or a second-line treatment in multiple immunocompetent mouse models of SCLC. The downstream effects of ATR inhibition was assessed by single-cell RNA sequencing, multicolor flow cytometry, western blot analysis, IHC, and genomic analysis. Results: In multiple immunocompetent SCLC mouse models, ATR inhibition (ATRi) remarkably enhanced the anti-tumor effect of PD-L1 blockade both as first- and second-line treatment regimen. Targeting ATR activated the cGAS/STING pathway, induced the expression of Type I and II interferon pathways, and caused significant infiltration of cytotoxic and memory/effector T-cells into tumors. Interestingly, ATRi also led to significant induction of MHC class I in SCLC in vitro and in vivo models. Analysis of pre- and post-treatment clinical samples from a proof-of-concept study of a first-in-class ATR inhibitor, M6620 (VX970, berzosertib), and TOP1 inhibitor topotecan, in patients with relapsed SCLCs validated the induction of MHC class I and interferon pathway genes, for the first time in this disease. Conclusion: Our findings highlight ATRi as a potentially transformative vulnerability of SCLC, paving the way for combination clinical trials with anti-PD-L1. Given the increasing importance of immunotherapy for the management of SCLC and that ATR inhibitors are already in clinical trials, combining an ATR inhibitor with PD-L1 blockade may offer a particularly attractive strategy for the treatment of SCLC and contribute to the rapid translation of this combination into the clinic. Citation Format: Triparna Sen. STING pathway activation by ATR inhibition potentiates the antitumor immune response to anti-PD-L1 antibody in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2265.